1. Field of the Invention
This invention relates to a novel cosmetic or dermatological delivery system having a variety of applications for delivery of topically applied active agents to the skin, to methods of preparing such delivery systems and to cosmetic or dermatological formulations in which the delivery systems may be incorporated. Of particular interest are multiphase cosmetic formulations such as gels, creams and lotions.
One difficulty with known cosmetic delivery systems is that of protecting labile compounds from reacting prematurely. Furthermore, certain biologically active substances, e.g. alphahydroxy acids, are known to benefit the skin by improving skin softness and appearance. However, many such actives tend to cause irritation because they have the capacity, if the local concentration is too high, to penetrate deeply through the stratum corneum to more sensitive living tissue. Accordingly, there is a need for a delivery system that can separate active agents from a formulating excipient or adjuvant and provide controlled release of the active substances at the point of application. It would also be advantageous to provide a delivery system for actives that permits localized concentration of actives at the point of delivery, for instance, at the skin's surface.
One approach is for actives to be bound to carrier molecules to provide a complex which will remain stable in cosmetic preparations. When the complex is applied to the skin, the active is released or dissociated from the delivery system and is absorbed into the skin to provide the desired effect. Such systems are known to the art, but they fail adequately to separate the actives from formulation ingredients. Nor do they provide a means for concentrating delivery of actives at a desired location, for example the skin's surface. Another problem encountered in delivering actives to the skin is that they may react undesirably with the delivery system itself. Cosmetic actives can be stabilized in suspensions and formulas as cosmetic preparations. However, formulating the thus stabilized actives requires elevated temperatures and varying pH levels which may modify the active and cause stability problems with the formulation.
Polyphenols such as procyanidin oligomers, are good examples of labile actives that are known to polymerize undesirably in reaction with common components of many cosmetic formulations. Polyphenols include catechins which are botanically derived antioxidant polyphenols extracted from grape seed, green tea and other woody plants. Catechins are useful for free radical scavenging in anti-ageing formulations to protect against the effects of ultraviolet light.
A multilayer particulate delivery systems for these and other active ingredients, and for controlled systemic release of drugs, is taught by Samain et al. in the U.S. Pat. No. 5,151,264. Samain et al. disclose what they describe as "biomimetic" carriers comprising an absorbent, solid, core of modified starch and an outer phospholipid coating which mimics a typical cellular membrane to avoid triggering the body's defenses to the incursion of foreign particles. Though Samain et al.'s multi-layer particles are very effective for many applications, it would be desirable to have a delivery system that provides additional options for release of the active at the delivery point or zone, and which permits quicker release at the skin's surface than is possible from Samain's dimensionally stable solid core particles.
Delivery systems for active substances having biologic or cosmetic activity, "actives" herein, can be either sustained release or controlled release systems. Sustained release systems release the active continuously from the moment of formulation. The active to be delivered is embedded within a matrix whose diffusion coefficient is low (lower than water for instance) so that the active slowly releases out of the matrix. This type of continuous release system is not suitable for cosmetic formulations because constant release of the active upon formulation of the system, for example into a cosmetic cream, creates instability affecting shelf life and effectiveness. In contrast, controlled release systems release the active when initiated by a particular event. The active is chemically or physically bound to a matrix in the controlled release system and is subsequently released when that bond is destroyed by an external event. For example, with the Samain et al. multilayer particles, the active ingredient is linked to the particle by means of ionic bonding. The release of the active is initiated by encounter with skin moisture, which has a relatively low ionic strength.
Gel forming polymers provide a delivery system by forming a matrix in which active substances can be entrapped. An example of a gel forming polymer is agar, also known as "agar-agar", a polysaccharide commonly used as a medium for electrophoresis and chromatography. It is known that agar can be formed into beads of various sizes for delivery of actives such as pharmaceutical drugs or even biological cells. A problem with agar beads is that they form a sustained release system which, as described above, is not suitable for cosmetic applications because release of the actives commences at formulation.
2. Description of Related Art Including Information Disclosed Under 37 CFR 1.97 and 37 CFR 1.98
Cini et al U.S. Pat. No. 5,457,093 discloses a sustained release gel formulation for delivering growth factors to wound sites, especially ophthalmic wounds. Various polysaccharide gels are used, including agar. Cini's gels are not intended for formulation into cosmetics and would presumably dissolve or disperse and fail to protect their actives, if subjected to mixing with an aqueous phase cosmetic vehicle. The actives are continuously released from the gel from the moment the gel is incorporated into a cosmetic formulation containing an aqueous phase. Accordingly, Cini's gel formulations cannot be used in cosmetic emulsions that are required to have significant shelf lives.
Modi U.S. Pat. No. 5,417,982 discloses a controlled release delivery system where a polymer-gel matrix comprised of two water-soluble polymers is incorporated into microspheres. Biodegradation of the microsphere matrix provides a controlled release oral or injection delivery system for administering therapeutic doses of proteins or polypeptides internally or systemically. Modi's system is apparently not intended for, and would not be suitable for, topical delivery and release of actives.
Rencher U.S. Pat. No. 5,314,915 provides a local anesthetic delivery system comprising a polymer blend of sodium carboxymethyl cellulose and xanthan gum or sodium alginate. Rencher's formulation is a continuous phase adhesive or teething gel, rather than being particulate, and does not provide a delivery system that will facilitate the incorporation of actives in a cosmetic or pharmaceutical formulation with good separation of the active from the formulation. Rencher's continuous phase system does not protect any adsorbed actives if incorporated into a cosmetic cream or lotion containing an aqueous phase.
Yarosh U.S. Pat. No. 5,077,211 discloses delivery of DNA repair enzymes in active form to living mammalian cells in situ by incorporating purified enzymes into liposomes which are diluted into media and added to target cells. The DNA enzymes are reportedly active topically and elsewhere to correct cellular deficiencies, stimulating generation of healthy tissue to replace aged or damaged skin. Yarosh's liposomes are prepared by rehydrating lipid mixture films with a concentrated, buffered, aqueous solution of the enzyme, agitating, sonicating and separating out the desired liposome spheres. Lipid mixtures used are based upon phosphatidyl choline (lecithin) as a primary ingredient, with dicetyl phosphate or stearylamine as secondary ingredients and with cholesterol an optional tertiary ingredient, see Examples 3 and 4.
According to Yarosh, the liposomes are incorporated into polyglycol gels, apparently at room temperature, for topical application, apparently under laboratory conditions. Consideration of Yarosh's delivery vehicles suggests that while they may be adequate for laboratory testing, they would not be suitable for commercial applications.
Yarosh U.S. Pat. No. 5,352,458 and Kripke et al. U.S. Pat. No. 5,302,389 disclose the use of Yarosh's DNA repair enzymes, prepared according to Yarosh '211, respectively for enhancing tanning by stimulating enhanced melanin production, and for suppressing UV-induced T-cell immune response and thence the associated redness, tenderness and inflammation.
Clearly, significant benefits might be obtained from a cosmetic or pharmaceutical formulation having a carrier to deliver such DNA repair, or other enzymes, in active form, for topical application to the skin by consumers with or without professional supervision. The difficulty is that enzymes are labile and subject to denaturing by formulation temperatures or pH conditions, or by reaction with cosmetic vehicles during the extended periods of shelf storage that are normal in the cosmetic and pharmaceuticals manufacturing and distribution chains.
Neither the liposomes described by Yarosh, nor the liposome gel would appear to offer sufficient protection to permit Yarosh or other enzymes to be formulated into consumer cosmetic products, such as creams, lotions or gels having adequate stability. The elevated processing temperatures, dispersing agents and extended shelf life required may decompose or denature not only the enzymes but their liposome carriers leading to unacceptable separation, loss of activity and the like.
There is accordingly a need for an esthetic cosmetic carrier for topically applied active agents that can protect labile actives such as botanical extracts, desquamating enzymes and the like, and deliver such agents to the skin in active form, while being suitable for formulation into traditional cosmetic vehicles. There are further needs for cosmetic or pharmaceutical delivery systems which offer separation of active from formulation ingredients and which can maintain that separation through typical formulation processes, especially those required for providing emulsions and for delivery systems which provide controlled release of actives at a delivery point and preferably also permit localized concentration of actives at the delivery point.